Clinical analyzer wash and method

ABSTRACT

A clinical analyzer has been described that includes a probe to aspirate a fluid. The probe is washed between aspirations to reduce carryover. The wash operation includes both an internal and an external wash, where the internal wash operation is terminated prior to terminating the external wash. In one example, the probe wash can be implemented on an integrated clinical chemistry/immunoassay analyzer.

RELATED APPLICATIONS

This patent arises from a continuation of U.S. application Ser. No.14/306,961, titled “Clinical Analyzer Wash and Method,” filed Jun. 17,2014, which is a continuation of U.S. Pat. No. 12/714,601 (now U.S. Pat.No. 8,759,106), titled “Clinical Analyzer Wash and Method,” filed Mar.1, 2010, which is a divisional application of and claims priority toU.S. application Ser. No. 10/158,495, titled “Clinical Tester Wash andMethod,” filed May 29, 2002. U.S. application Ser. Nos. 14/306,961;12/714,601; and 10/158,495 are hereby incorporated by reference in theirentireties.

FIELD OF THE DISCLOSURE

The present disclosure relates generally to clinical test equipment andin particular the present disclosure relates to reduction of samplecarryover in clinical test equipment.

BACKGROUND

Although various known clinical analyzers for chemical, immunochemicaland biological testing of samples are available, clinical technology israpidly changing due to increasing demands in the clinical laboratory toprovide new levels of service. These new levels of service must be morecost effective to decrease the operating expenditures such as labor costand the like, and must provide shorter turnaround time of test results.Modernization of analytical apparatus and procedure demandsconsolidation of workstations to meet the growing challenge placed onclinical laboratories.

Generally, analysis of a test sample involves the reaction of testsamples with one or more reagents with respect to one or more analyteswherein it is frequently desired that the analysis be performed on aselective basis with respect to each test sample. Automated clinicalanalysis systems analyze a test sample for one or more characteristics.Automated clinical analyzers also provide results much more rapidlywhile frequently avoiding operator or technician error, thus placingemphasis on accuracy and repeatability of a variety of tests. Automatedclinical analyzers presently available for routine laboratory testsinclude a transport or conveyor system designed to transport containersof sample liquids between various operating stations.

Some of the presently available automated clinical analyzers, such asautomated immunoassay analyzers, utilize procedures involving a varietyof different assay steps. A robotic arm automatically processes the testsamples with a probe and a carousel, or robotic track, which positionsthe samples for processing. A typical analyzer has a sample probe tosample fluids and deposit the samples in a reaction vessel. One or morereagents are added to the vessel using reagent probes. Sample andreagent probe arms include probes that can be moved between sample orreagent locations, the reagent vessel and wash stations.

Clinical chemistry and immunoassay analyzers have traditionally beenstandalone systems. These systems can be combined using a commontransport system to provide a more efficient integrated system. Previousstandalone chemistry analyzers did not require sample-to-samplecarryover performance requirements of an integrated clinical chemistryand immunoassay system. As laboratories integrate automated analyticalsystems, reduction of between-sample carryover becomes a critical goal.Many companies have elected to overcome this problem through use ofdisposable probe tips, but this approach is costly, wasteful and lessreliable. Another safeguard is to prioritize test sequencing such thatimmunoassay sampling is done prior to all chemistry tests. This approachimpacts chemistry turnaround time and lowers total workflow throughput.Yet another method to reduce sample carryover is to flush the systemwith large amounts of fluids (buffer, water, detergents).

For the reasons stated above, and for other reasons stated below whichwill become apparent to those skilled in the art upon reading andunderstanding the present specification, there is a need in the art fora reduction in sample carryover in clinical test equipment.

SUMMARY

The above-mentioned problems with sample carryover and other problemsare addressed by the present disclosure and will be understood byreading and studying the following specification.

In one example, a clinical analyzer comprises a probe having an interiorregion and an exterior surface. The probe is used to selectivelyaspirate a fluid into the interior region. A first wash mechanism iscoupled to the probe to dispense a wash fluid through the interiorregion of the probe for a first predetermined period. A second washmechanism is located to dispense the wash fluid on the exterior surfaceof the probe for a second predetermined period. The second predeterminedperiod extends beyond the first predetermined period.

In another example, a method of cleaning a probe comprises flushing aninterior region of the probe with a wash fluid for X seconds, andsimultaneously flushing an exterior surface of the probe with the washfluid for Y seconds, wherein Y is greater than X.

A method for reducing sample carryover in an integrated chemistry andimmunoassay analyzer comprises aspirating a first test sample from afirst sample container using a probe, depositing the first test sampleinto a reaction vessel and performing a chemical analysis of the testsample. The probe is washed by pumping a wash fluid through an interiorregion of the probe and pumping the wash fluid on the exterior of theprobe. The pumping of the wash fluid into the interior region isterminated prior to terminating the pumping of the wash fluid to theexterior. A second test sample is then aspirated from a second samplecontainer using the probe.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a perspective view of an example clinical analyzer;

FIG. 1B is a clinical chemistry analyzer of the analyzer of FIG. 1A;

FIG. 1C is an immunoassay analyzer of the analyzer of FIG. 1A;

FIG. 2 illustrates a probe arm of the clinical analyzer of FIG. 1; and

FIG. 3 is a simplified cross-section of a probe in a wash station.

DETAILED DESCRIPTION

In the following detailed description of the preferred examples,reference is made to the accompanying drawings, which form a parthereof, and in which is shown by way of illustration specific preferredexamples in which the disclosure may be practiced. These examples aredescribed in sufficient detail to enable those skilled in the art topractice the disclosure, and it is to be understood that other examplesmay be utilized and that logical, mechanical and electrical changes maybe made without departing from the spirit and scope of the presentdisclosure. The following detailed description is, therefore, not to betaken in a limiting sense, and the scope of the present disclosure isdefined only by the claims.

The term “test sample”, as used herein, refers to a test material thatcan be used directly as obtained from a source or following apretreatment to modify the character of the sample. The test sample canbe derived from any biological source, such as physiological fluid,including, whole blood, serum, plasma, saliva, ocular lens fluid,cerebral spinal fluid, sweat, urine, milk, ascites fluid, raucous,synovial fluid, peritoneal fluid, amniotic fluid or the like.

The term “carryover” refers to cross-contamination or contact transferbetween test samples. Carryover is a byproduct of using a common sampleprobe for multiple test samples.

Between-sample carryover is a critical factor to ensure result integrityon automated analytical systems. Immunoassay analyzers traditionallymeet a sample-to-sample carryover goal of less than 0.1 ppm. Clinicalchemistry systems utilize methodologies that are less sensitive andrarely characterized using carryover requirements to this level. Aslaboratories consolidate analytical systems, however, the between-samplecarryover demands for immunoassay analyzers become applicable toclinical chemistry systems as well. Achieving a between-sample carryovergoal of less than 0.1 ppm for an integrated immunoassay and clinicalchemistry system can impact marketability of other variables includingspecimen throughput, system consumables, test prioritization, and samplepre-aliquoting.

Extensive research on an integrated system of an example of the presentdisclosure identified critical variables associated withsample-to-sample carryover. High-speed video was used for qualitativecharacterization of the sample probe wash while concentrated samples ofhepatitis surface-antigen (HbsAg) were used to quantitatively assesscarryover performance. A probe wash protocol of an example of thedisclosure passes the between-sample carryover limit of 0.1 ppm withoutsample pre-aliquoting, use of additional consumables, testprioritization, or significant impact to system specimen throughput.Critical variables include clinical chemistry sampling/aspirationvolumes and external sample probe wash duration, sequencing relative tothe internal sample probe wash. Other variables include positioning ofthe sample probe within the sample wash cup, sample wash cup design andexternal sample wash flow volumes/rates.

An example of a wash protocol dictates the between sample wash mechanismbased on clinical chemistry sampling volume. The wash includes anexternal wash and an internal wash of the sample probe. All specimenswith a maximum chemistry sampling volume below a predetermined threshold(such as 15 μL or less) are effectively washed using an extended singlecycle wash mechanism. It is noted that a ‘dummy’ fluid volume may beaspirated in addition to the fluid sample volume. The dummy volumeprovides a buffer between the sample fluid and residual fluid in theprobe. The dummy volume is not included in the sample volume levelsdescribed herein. The extended single cycle wash mechanism utilizes aone second external probe wash that ends 100 ms after the internal probewash. This timing relationship between the internal and external washsequencing is particularly crucial for acceptable carryover performance.Specimens that are processed with chemistry sampling volumes exceedingthe threshold (15.1 μL or more) are washed using the same extendedsingle cycle wash mechanism but also undergo an additional 3.2 secondsof supplemental external wash. The wash protocol of the presentdisclosure, as explained below, is not limited to a specific timingduration or over-lap time between the termination of internal andexternal washes.

Between-Sample Carryover was quantitatively evaluated using recombinantsamples of concentrated hepatitis surface-antigen (HbsAg) in a pooledhuman serum matrix. Each concentrated HBsAg sample (with approximateimmuno-reactivity of 4 mg/mL) was followed by pooled normal human serum(pre-screened non-reactive for HbsAg) and processed on a chemistryanalyzer. The pooled human serum samples were evaluated on animmunoassay analyzer for HbsAg activity. Results were compared againstserial dilutions of the concentrated stock. If the pooled human serumresults exceeded that of the 0.1 ppm dilution of the concentrated stock,a test run was considered a failure. The magnitude of the failure wascalculated by converting the reported concentration of the serumdiluents into units of ppm from the reference dilution. Test conditionswere created to represent worst-case performance and test resultconfidence. The clinical chemistry sample volume was defined at 35 μL, atypical maximum sample volume for a chemistry application. HbsAg sampleswere processed in duplicate to ensure result integrity.

Results demonstrated a sample carryover performance trend associatedwith sample probe aspiration volume. As the clinical chemistry samplevolume increases, between-sample carryover failures also increase. Mostsystems fail between-sample carryover with a frequency higher than 50%(without optimization critical parameters) at the maximum clinicalchemistry sampling volume of 35 μL. The relationship between samplevolume and sample-to-sample carryover performance is significant tounderstanding the mode of failure. This is because trending demonstratesthat internal contamination of the sample probe has an impact onsample-to-sample carryover. The sample probe aspirates a test samplefrom a sample tube and immediately dispenses the sample volume into areaction vessel prior to entrance into a wash station. Anover-aspiration or dummy volume is dispensed at the wash station butthis volume is consistent and independent of chemistry sample volume(under the protocol test conditions). Since the frequency of thecarryover increases with chemistry sample volume and since this samplevolume is dispensed prior to external wash of the probe, it wastheorized that the source of the carryover (leading to thebetween-sample failures) resulted from internal contamination of thesample probe. This theory was supported by a supplemental investigationthat demonstrated that carryover failures were still prevalent withoutany dummy/over aspiration being dispensed at the sample wash station.Residual carryover remained on the external surface of the sample probefollowing sample probe washing, even when the probe did not dispense anyconcentrated sample at the wash station. The frequency of samplecarryover failures can be reduced using supplemental probe washes.Unfortunately, supplemental washes require additional instrument cyclesthat can degrade system specimen throughput.

A second variable to carryover performance is wash sequencing at thesample wash station. Further analysis of wash conditions at the samplewash station lead to a study evaluating external wash sequencingrelative to the internal wash. Success of the probe wash was lessdependent on the external wash duration than it was on the stopsequencing of the external wash relative to the internal wash. If theinternal wash stops after the external wash, carryover performance issignificantly worse than if the external wash if ends after the internalwash. This relationship supports a theory that internal contamination ofthe probe is a source for the external between-sample carryover. Onewash protocol utilizes a one second external probe wash that extendsbeyond the stop time of the internal wash to improve carryoverperformance at low sample volumes. A supplemental washing that wouldhave required an additional instrument cycle is not required to meetcarryover performance criteria.

Further studies demonstrated additional variables associated withbetween-sample carryover performance. These include wash cup design,hardware alignment at the sample wash station, and wash flowrates/volume. These variables are significant and require optimizationfor carryover performance. Failure to optimize these parameters cancause carryover failures. However, optimization, of these parameterswill not create a passing condition without control of the criticalvariables of chemistry sampling volume and wash sequencing.

Referring to FIG. 1A, a perspective view of a simplified integratedclinical test system 100 of an example of the present disclosure. Thetest system includes a clinical chemistry analyzer 102 and animmunoassay analyzer 104, see FIGS. 1B and 1C for more detail. The twoanalyzers share a common sample transporter 106 that allows linearmovement of test sample tubes 108 between the two analyzers.

Each analyzer has a sample probe arm 110/112 that includes a sampleprobe 114 (see FIG. 2). The sample probe arms 110/112 can move in both ahorizontal arc and vertical directions. The sample probe 114 aspirates atest sample from tube 108 located on the transporter 106. The sampleprobe 114 is then moved to a sample vessel (not shown) and deposits theaspirated sample. After the sample has been discharged from the sampleprobe 114, the sample probe arm 110/112 moves to a wash station 120where the sample probe 114 is washed. The sample vessel is moved to alocation where a reagent is added to the sample by a reagent probe of areagent probe arm 122. The reagent probe arm 122 is movable between areagent location, the sample vessel and the wash station. The samplevessel may receive additional reagents and is then subjected tochemistry testing, as known to those skilled in the art. A secondreagent probe of a second reagent probe arm 123 can be included toprovide a second reagent to the sample vessel.

The sample tube 108 located on the transporter 106 is then moved to alocation near the immunoassay analyzer 104, FIG. 1C. The immunoassayanalyzer is similar in operation to the clinical chemistry analyzer inthat a test sample from the sample tube is aspirated using sample probe114 of sample probe arm 110/112. The sample probe arm 110/112 then movesto a sample vessel (not shown) and the sample probe 114 deposits theaspirated sample. After the sample has been discharged from the sampleprobe 114, the sample probe arm 110/112 moves to a wash station (notshown) where the sample probe 114 is washed. The sample vessel is movedto a location where a reagent is added to the sample by a reagent probeof a reagent probe arm 115. The reagent probe arm 115 is movable betweena reagent location, the sample vessel and the wash station. The samplevessel may receive additional reagents and is then subjected to testing,as known to those skilled in the art. It is clear that sample carryover,or contamination, can occur if the sample probes 114 are not cleanedbetween aspirations of different test samples.

FIG. 2 illustrates a sample probe arm 110. The sample probe arm 110includes a sample probe 114 that can be moved about a horizontal arc andin a vertical direction. The sample probe 114 has a hollow bore thatallows aspiration of a fluid and the subsequent introduction of a washfluid. The mechanics of the sample probe arm 110 are not described indetail herein, but are generally known to those skilled in the art. Forpurposes of understanding the disclosure, the sample probe arm 110 iscontrollable to regulate the amount of sample aspirated and the amountand duration of wash fluid that flows through the sample probe 114.

Referring to FIG. 3, a cross-sectional view of a sample probe 114 andwash cup 126 are illustrated. The size and shape of the sample probe 114and wash cup 126 are illustrative only and not intended to reflectactual designs or sizes. Those skilled in the art with the benefit ofthe present description will appreciate that the designs of the sampleprobe 114 and wash cup 126 can vary without departing from the presentdisclosure. The sample probe 114 is substantially tube-shaped andincludes an exterior surface 132 and an interior surface 130. Aninterior wash dispenser 136, or nozzle, is located to discharge a washfluid into the interior region of the sample probe 114. During a washoperation, the sample probe 114 is vertically positioned in the wash cup126. The wash cup 126 includes one or more exterior wash dispensers 138,or nozzles, positioned to spray a wash fluid toward a center region ofthe wash cup 126 and onto the exterior surface 132 of the sample probe114.

The wash fluid pumped through the interior region of the sample probe114 and on its exterior surface 132 is the same fluid and depends uponthe material that is to be removed from the sample probe 114. The washfluid can be located in a common reservoir 140 and pumped to the nozzlesusing separate pumps 142 and 144. Alternately, a single pump andcontrollable valves can be used to pump the wash fluid to the nozzles.The present disclosure is not limited to a specific pump design,provided the termination of the flow of the internal fluid and theexternal fluid can be separately controlled by pump(s) controller 150.The term ‘pump’ is intended to include any mechanism that allows forcontrolled movement of a liquid, such as the wash fluid.

As explained above, a given probe needs to be sufficiently cleanedbetween aspirations to reduce liquid carryover. The liquid carryover canbe that of a test sample or a reagent depending upon the probe. Theinternal wash is terminated prior to terminating the external wash. Thistermination overlap significantly reduces liquid carryover and allowsclinical chemistry analyzers to meet the restrictive specifications ofimmunoassay analyzers. One example wash for chemistry sampling volumebelow a predetermined threshold (such as 15 μL or less) includes a onesecond external sample probe wash that ends 100 ms after the internalsample probe wash ends. The external wash can begin prior to theinternal wash without departing from the present disclosure.

The present disclosure is not limited to an integrated clinicalchemistry/immunoassay analyzer, and other analytical systems can utilizethe relationship of between-sample carryover performance to improvesample wash parameters. This includes other clinical chemistry andimmunoassay systems as well as hematology and other methodologies. Thewash method can also be used utilized for reagent carryover washing,sample pretreatment instrumentation, and with laboratory automationsystems.

CONCLUSION

A clinical analyzer has been described that includes a probe to aspiratea fluid. The probe is washed between aspirations to reduce carryover.The wash operation includes both an internal and an external wash, wherethe internal wash operation is terminated prior to terminating theexternal wash. In one example, the probe wash can be implemented on anintegrated clinical chemistry/immunoassay analyzer.

Although specific examples have been illustrated and described herein,it will be appreciated by those of ordinary skill in the art that anyarrangement, which is calculated to achieve the same purpose, may besubstituted for the specific example shown. This application is intendedto cover any adaptations or variations of the present disclosure.Therefore, it is manifestly intended that this disclosure be limitedonly by the claims and the equivalents thereof.

What is claimed is:
 1. A method comprising: determining a samplingvolume of a test sample aspirated by a probe of an analyzer; flushing aninterior region of the probe with wash fluid for X seconds; and flushingan exterior surface of the probe with the wash fluid for Y seconds, theflushing of the interior region and the exterior surface occurring atleast partially simultaneously, wherein the flushing of the exteriorsurface is to terminate after the flushing of the interior region is toterminate, and wherein Y is based on the sampling volume.
 2. The methodof claim 1, wherein Y is a first duration of time if the sampling volumeis less than a threshold, and Y is a second duration of time if thesampling volume is greater than the threshold, the second duration oftime being greater than the first duration of time.
 3. The method ofclaim 2, wherein the second duration of time is about three times longerthan the first duration of time.
 4. The method of claim 1, wherein theflushing of the exterior surface is to terminate about 0.1 second afterthe flushing of the interior region is to terminate.
 5. The method ofclaim 1, wherein the flushing of the exterior surface starts prior tothe flushing of the interior region.
 6. The method of claim 1, whereindetermining the sampling volume comprises subtracting a volume of bufferfluid, which is aspirated prior to an aspiration of the sampling volume,from a total aspirated volume.